Oxidative stress (OS) is recognized as disturbance of cellular equilibrium between reactive oxygen species (ROS) formation and their elimination by antioxidant defense systems. One example of ROS-mediated damage is generation of potentially mutagenic DNA precursor, 8-oxodGTP. In human cells genomic 8-oxodGTP incorporation is prevented by the MutT homologue 1 (MTH1 or hMTH1 for human MTH1) protein. It is well established that malignant cells, including thyroid cancer cells, require hMTH1 for maintaining proliferation and cancerous transformation phenotype. Above observations led to the development of hMTH1 inhibitors as novel anticancer therapeutics. In the current study we present extensive analysis of oxidative stress responses determining sensitivity to hMTH1 deficiency in cultured thyroid cells. We observe here that hMTH1 depletion results in downregulation of several glutathione-dependent OS defense system factors, including GPX1 and GCLM, making some of the tested thyroid cell lines highly dependent on glutathione levels. This is evidenced by the increased ROS burden and enhanced proliferation defect after combination of hMTH1 siRNA and glutathione synthesis inhibition. Moreover, due to the lack of data on hMTH1 expression in human thyroid tumor specimens we decided to perform detailed analysis of hMTH1 expression in thyroid tumor and peri-tumoral tissues from human patients. Our results allow us to propose here that anticancer activity of hMTH1 suppression may be boosted by combination with agents modulating glutathione pool, but further studies are necessary to precisely identify backgrounds susceptible to such combination treatment.

氧化应激 (OS) 被认为是活性氧 (ROS) 形成与抗氧化防御系统消除它们之间细胞平衡的紊乱。ROS 介导的损伤的一个例子是产生潜在的诱变 DNA 前体 8-oxodGTP。在人类细胞中，基因组 8- oxodGTP的掺入被M ut T同系物1阻止（人类 MTH1 的 MTH1 或 hMTH1）蛋白质。众所周知，包括甲状腺癌细胞在内的恶性细胞需要 hMTH1 来维持增殖和癌变表型。上述观察导致 hMTH1 抑制剂作为新型抗癌疗法的发展。在目前的研究中，我们对氧化应激反应进行了广泛的分析，以确定培养的甲状腺细胞对 hMTH1 缺陷的敏感性。我们在这里观察到hMTH1耗尽导致几种谷胱甘肽依赖性 OS 防御系统因子的下调，包括GPX1和GCLM, 使得一些被测试的甲状腺细胞系高度依赖于谷胱甘肽水平。在hMTH1 siRNA 和谷胱甘肽合成抑制相结合后，ROS 负荷增加和增殖缺陷增强证明了这一点。此外，由于缺乏人类甲状腺肿瘤标本中 hMTH1 表达的数据，我们决定对人类患者的甲状腺肿瘤和肿瘤周围组织中的 hMTH1 表达进行详细分析。我们的结果使我们能够在这里提出，hMTH1 抑制的抗癌活性可以通过与调节谷胱甘肽池的药物联合使用来增强，但需要进一步的研究来精确识别对这种联合治疗敏感的背景。